Increased oxygen consumption rate observed in primary cultures of erythropoietin stimulated erythroid progenitor cells suggest a link between increased metabolism and erythropoietin stimulated erythroid differentiation. In addition, erythropoietin stimulation increases glucose uptake in erythroid progenitor cells. Interestingly, mice (C57Bl6) treated with erythropoietin demonstrated the expected an increase in hematocrit accompanied by a decrease in blood glucose level. This change in blood glucose is accompanied by an improvement in glucose tolerance and a decrease in fat mass. Primary erythroid progenitor cell cultures treated with erythropoietin exhibit a dose dependent increase in glucose uptake (but no change in fetal hemoglobin), suggesting that erythropoietin stimulated erythropoiesis may increase glucose metabolism in vivo and contribute to decrease in body weight. However, mice with erythropoietin receptor restricted to hematopoietic tissue demonstrate the increase in red blood cell production, but little change in blood glucose or body weight compared with saline control. These mice also show a decrease whole body metabolic homeostasis with decreased ambulatory activity and oxygen consumption, providing evidence that non-hematopoietic tissues contribute in a major way to regulation of circulating blood glucose with erythropoietin treatment . These data suggest that erythropoietin administration in mice increases red blood cell production as well as metabolism, that increasing erythropoietin level in culture stimulates glucose uptake, but that erythropoietin stimulated erythropoiesis is only a minor contributor to whole metabolic homeostasis.